Sleep is a global state and its control mechanisms are manifested at every level of biological organization- from genes and intracellular mechanisms, to networks of cell populations, to phenotypes at the organismal level. They include (but are not limited to) arousal, motor control, autonomic function, behavior, and cognition. We live in a sleep deprived society. Prolonged sleep loss impairs temperature control, dietary metabolism, immune function, and eventually leads to death. Sleep deprivation increases an individual's risk of cancer, metabolic syndrome, psychiatric, and other disorders. Understanding the biological basis of sleep in humans is an extremely difficult challenge since the biological determinants of our sleep are affected by behavior and other factors including life-style choices, socio-economic status, health, employment, school, and exogenous chemicals like caffeine and alcohol. Sleep and circadian function are distinct processes that interact in living organisms. Sleep is controlled by at least two processes: a circadian pacemaker (the clock) ticking with periodicity of ~24 hours, and a homeostatic drive that increases during wakefulness and dissipates during sleep. Despite of the fact that we spend around one third of our life in the state of sleep, we understand almost nothing about regulatory mechanisms governing sleep quantity. A unique opportunity presented itself when we identified independent families with a dramatically reduced biological need for sleep. Identification of new subjects and expanding our collection of these families will establish a foundation for us to begin probing the molecular regulatory mechanisms of sleep homeostasis. Recently, we reported the first mutation that causes this short-sleep phenotype. Interestingly, this mutation gave a similar short sleep phenotype in human, mouse, and fly. All the genes identified in this study will therefore become entry points for us to unravel the enigmatic sleep related mechanisms. Ultimately, combining the knowledge from studies in multiple genes and in humans and model organisms will lead to a better understanding of sleep and its relationship to health and disease. PUBLIC HEALTH RELEVANCE: Project Narrative We humans spend close to one third of our life in the state of sleep but our understanding of its regulation remains limited. A very unique opportunity presented itself to us recently when we identified the first human genetic form of sleep "need" variation, and the gene/mutation that leads to natural short sleep syndrome in this family. This proposal outlines a plan to expand our current resource and to identify additional genes that are in sleep regulation pathways. These resources and information will tremendously enhance our understanding of the mechanisms that regulate our sleep. This will have important implications for the mechanism through which sleep alterations and sleep deprivation increase risk of many diseases.